The long-term goal of this study is to identify mechanisms of viral inhibition of host immune defenses against infection. The poxvirus family includes some of the most virulent of all human pathogens. In part, the pathogenicity of these viruses results from their abilities to counter host defenses against infection. Cowpoxvirus, a virus closely related to smallpoxvirus, encodes about two hundred proteins, many of which are involved in the inhibition of immune processes. In particular, this virus effectively inhibits inflammatory processes. Because of these properties, it provides a unique system for investigation of these processes. This system has already enabled us to identify seven viral cytokine-response modifiers: CrmA, an inhibitor of several caspases and granzyme B: a soluble, interleukin-1 receptor; soluble, secreted, TNF receptors of three types: CrmB, CrmC, and CrmD; a soluble, secreted receptor for beta-chemokines; a soluble, secreted receptor for the CD30 ligand. His results suggest that cowpox virus encodes numerous additional cytokine-response modifiers and inhibitors affecting both non-specific and specific immune defenses. In particular, he has found that poxviruses inhibit the activation of NF-kB, a transcription factor of cardinal importance in a wide range of immune and pathological processes. The immediate specific aims of this study are as follows: (1) To determine the mechanisms by which poxviruses inhibit the activation of NF-kB. (2) To identify additional mechanisms employed by cowpoxvirus to counter immune responses. (3) To determine the mechanism of gene expression-dependent uncoating of poxviruses. Knowledge of the mechanisms involved in the effective poxviral inhibition of host defenses against infection should assist the development of new therapies for a variety of conditions associated with infectious diseases, inflammatory diseases, autoimmune diseases, cancers, and organ transplantation.